Double PFS rate of Lumakras in comparison with docetaxel in KRAS G12C mutated NSCLC

There are three genes related to human tumors in the RAS gene family. Harvey rat sarcoma viral oncogene (HRAS), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Neuroblastoma rat sarcoma viral oncogene (NRAS), which are located on chromosomes 11, 12, and 1. Among them, KRAS is one of the most frequent oncogenes in NSCLC, a molecular subset that is characterized by historical disappointments in targeted treatment approaches. Unlike other important mutational subtypes of NSCLC, preclinical work supports the hypothesis that KRAS mutations may be vulnerable to immunotherapy approaches.

The most common type of KRAS mutation is KRAS G12C. KRAS G12C allele inhibitors trap oncoproteins in an inactive state by inhibiting the reactivation of exchanged nucleotides, thereby blocking the proliferation of tumor cells that depend on the protein’s signaling pathways.

For the study, patients were randomized to receive either oral sotorasib at 960 mg per day (n = 171) or intravenous (IV) docetaxel at 75 mg/m² every 3 weeks (n = 174). All patients had received prior platinum-based chemotherapy and a checkpoint inhibitor either concurrently or sequentially. Patients with active brain metastases were excluded from the study, although a history of brain metastases was allowed, Johnson noted. After the median follow-up of 17.7 months, the 12-month PFS rate was 24.8% vs. 10.1% with LUMAKRAS vs. docetaxel docetaxel. The median PFS was 5.6 months vs. 4.5 months (Hazard Ratio: 0.66 [95% CI: 0.51, 0.86]). The median OS was found to be at a lower side in the sotorasib group with 10.6 months vs. 11.3 months for docetaxel. Around 36% of patients in the sotorasib arm received a subsequent therapy at crossover compared with 42% in the docetaxel arm. The ORR with sotorasib was 28.1% compared with 13.2% with docetaxel (p < 0.001). When also considering patients with stable disease, the overall DCR was 82.5% for sotorasib compared with 60.3% with docetaxel. Any degree of tumor shrinkage was seen in 80.4% of patients treated with sotorasib compared with 62.8% in those treated with docetaxel. The median percent change in tumor size for responders was 58.8% with sotorasib vs. 48.5% with docetaxel. The median time to response was 1.4 months vs. 2.8 for sotorasib and docetaxel, respectively. Median duration of response was 8.6 months with sotorasib compared with 6.8 months for docetaxel.

TRAEs leading to discontinuation were experienced by 9.5% of patients in the sotorasib arm compared with 11.3% with docetaxel. The most common any-grade TRAEs between sotorasib and docetaxel, respectively, were diarrhea (33.7% vs. 18.5%), nausea (14.2% vs. 19.9%), alanine aminotransferase (ALT) increase (10.1% vs. 0%), aspartate aminotransferase (AST) increase (10.1% vs. 0%), and fatigue (6.5% vs. 25.2%). The most common grade 3 or greater TRAEs with sotorasib were diarrhea (11.8%), ALT increase (7.7%), and AST increase (5.3%).

Conclusion- KRAS, which was long considered undruggable, had bagged it's only drug approved till date for KRAS mutated NSCLC patients that is Lumakras (sotorasib). As per the results published at ESMO 2022, it could be easily concluded that sotorasib showed statistical significance and superiority in the confirmatory CodeBreak200 study. The CodeBreak200 study has marked first success for a KRAS inhibitor in a randomized clinical trial and can also move up the potential conversion of Lumakras’ current FDA approval in the second-line NSCLC into a full nod, which will ultimately result in trouble for Mirati’s KRAS contender adagrasib. Just like Amgen, Mirati is also hoping to get an initial accelerated approval based on the shrinkage of tumor data but, the full approval for Lumakras will close the accelerated pathway for adagrasib and also may delay the FDA nod until its own randomized Phase III readout. Also, both of these drugs are being tested with Keytruda in the newly diagnosed NSCLC patients which is also an important study to keep a close eye on. Few months back, Amgen gave a first look at Lumakras-Keytruda data in NSCLC which showed high discontinuation rates which raised questions around the viability of the combination. But, despite all these concerns, Amgen is moving forward with a low 240-mg dose of Lumakras before adding Keytruda in a dose-expansion phase of the early-stage study in treatment-naïve NSCLC patients.

Expert Opinion: “The PFS rate doubled and the PFS benefit was seen across all subgroups tested. Likewise, the secondary end points of objective response rate [ORR], disease control rate [DCR], time to response, and duration of response were all significantly improved in favor of sotorasib. In my opinion, this supports sotorasib as a new second-line standard for patients with KRAS G12C–mutated NSCLC.”

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